The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity
The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity
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DOI：
10.1016/j.molcel.2012.04.014
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发表时间：
2012-06-29
期刊：
影响因子：
16
通讯作者：
Gyrd-Hansen, Mads
中科院分区：
文献类型：
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作者：
Damgaard, Rune Busk;Nachbur, Ueli;Gyrd-Hansen, Mads
核苷酸结合和寡聚化结构域（NOD）样受体构成了抵御入侵细菌的第一道防线。X连锁细胞凋亡抑制因子（XIAP）参与细菌感染的控制，XIAP的突变与X连锁证明性综合征2型（XLP-2）中的免疫缺陷有因果关系。在这里，我们证明了XIAP的RING结构域是NOD 2信号传导所必需的，并且XIAP有助于实验小鼠炎症诱导的肝炎的恶化。我们发现XIAP使RIPK 2泛素化，并将线性泛素链组装复合物（LUBAC）募集到NOD 2。我们进一步表明，LUBAC活性是NOD 2刺激后NF-κ B有效激活和促炎细胞因子分泌所必需的。值得注意的是，XLP-2衍生的XIAP变体具有受损的泛素连接酶活性，不能使RIPK 2泛素化，并且不能促进NOD 2信号传导。我们的结论是XIAP和LUBAC构成了NOD 2介导的炎症信号中必不可少的泛素连接酶，并提出NOD 2信号的失调有助于XLP-2的发病机制。
Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked demonferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-kappa B activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.